Effective treatment for TBI is one of the greatest unmet needs in public health. Failed clinical trials for TBI have been attributed in part to the heterogeneity of injury, the symptom-based diagnosis and classification methods for TBI, and the lack of pharmacokinetic analyses to determine optimal dosing of potential therapies. The symptom based Glasgow Coma Scale (GCS) is a major component of determining the presence of TBI early after injury but is subject to significant limitations resulting in inaccurat determination of brain injury in up to 20% of cases. As a result, biomarkers of structural brain injury have been increasingly studied to identify and classify TBI, and to predict outcome after TBI. Our overall hypothesis is that levels of circulating brain-specific biomarkers after acute moderate or severe TBI reflect the presence and severity of TBI and can be used to stratify patients, measure treatment response and predict outcome. We will examine 3 promising brain-specific biomarkers (glial fibrillary acidic protein [GFAP] from astrocytes, Ubiquitin C-Hydrolase-L1 [UCH-L1] from neurons, and the 150-kDA aII-spectrin breakdown product [SBDP150] from axons) in patients with moderate or severe acute TBI enrolled in the Prehospital Tranexamic Acid for TBI Trial. This trial, funded by the DoD and NHLBI, will randomize 1002 patient with moderate or severe TBI to receive one of two dosing regimens of TXA or placebo in the prehospital setting in 10 centers across the US and Canada using the infrastructure of the Resuscitation Outcomes Consortium. We will test this hypothesis with the following specific aims. 1. To determine if initial values, or trends in serially measured circulating brain-specific biomarkers (GFAP, UCH-L1, SBDP150) are associated with the presence of intracranial hemorrhage, injury pattern and severity, and 28-day mortality after moderate or severe TBI. 2. To determine if circulating brain-specific biomarkers (GFAP, UCH-L1, SBDP150) are associated with treatment arm allocation, serum TXA level, and long-term outcome as measured by the GOS-E 6 months after injury in moderate or severe TBI. 3. To determine if circulating brain-specific biomarkers (GFAP, UCH-L1, SBDP150) improve long-term outcome prediction after moderate or severe TBI. In addition, we propose to leverage the resources of this large clinical trial to create a genomic and transcriptomic specimen repository from samples obtained at sequential time points very early after injury in this patient cohort. With this study we will be ale to refine the diagnosis of TBI to enable early identification of specific patterns of brain injury hat can be linked to appropriate therapeutic interventions for targeted inclusion into clinical trials. Furthermore, we may expand upon existing prediction models to support both clinical practice and TBI research, including the design and analysis of randomized trials. Finally, we may also establish brain-specific biomarkers as an effective method of monitoring response to treatment in TBI that could have widespread use both clinically and in interventional TBI trials.